Kwon So Mee, Kang Shin-Hyuk, Park Chul-Kee, Jung Shin, Park Eun Sung, Lee Ju-Seog, Kim Se-Hyuk, Woo Hyun Goo
Department of Physiology, Ajou University School of Medicine, Suwon, Republic of Korea; Graduate School of Biomedical Science, Ajou University School of Medicine, Suwon, Republic of Korea.
Department of Neurosurgery, Korea University College of Medicine, Seoul, Republic of Korea.
PLoS One. 2015 Oct 14;10(10):e0140528. doi: 10.1371/journal.pone.0140528. eCollection 2015.
Previously, transcriptomic profiling studies have shown distinct molecular subtypes of glioblastomas. It has also been suggested that the recurrence of glioblastomas could be achieved by transcriptomic reprograming of tumors, however, their characteristics are not yet fully understood. Here, to gain the mechanistic insights on the molecular phenotypes of recurrent glioblastomas, gene expression profiling was performed on the 43 cases of glioblastomas including 15 paired primary and recurrent cases. Unsupervised clustering analyses revealed two subtypes of G1 and G2, which were characterized by proliferation and neuron-like gene expression traits, respectively. While the primary tumors were classified as G1 subtype, the recurrent glioblastomas showed two distinct expression types. Compared to paired primary tumors, the recurrent tumors in G1 subtype did not show expression alteration. By contrast, the recurrent tumors in G2 subtype showed expression changes from proliferation type to neuron-like one. We also observed the expression of stemness-related genes in G1 recurrent tumors and the altered expression of DNA-repair genes (i.e., AURK, HOX, MGMT, and MSH6) in the G2 recurrent tumors, which might be responsible for the acquisition of drug resistance mechanism during tumor recurrence in a subtype-specific manner. We suggest that recurrent glioblastomas may choose two different strategies for transcriptomic reprograming to escape the chemotherapeutic treatment during tumor recurrence. Our results might be helpful to determine personalized therapeutic strategy against heterogeneous glioma recurrence.
此前，转录组分析研究已揭示了胶质母细胞瘤的不同分子亚型。也有研究表明，胶质母细胞瘤的复发可能是通过肿瘤的转录组重编程实现的，然而，其特征尚未完全明确。在此，为了深入了解复发性胶质母细胞瘤分子表型的机制，我们对43例胶质母细胞瘤进行了基因表达谱分析，其中包括15对原发性和复发性病例。无监督聚类分析揭示了G1和G2两种亚型，分别以增殖和神经元样基因表达特征为特点。原发性肿瘤被归类为G1亚型，而复发性胶质母细胞瘤表现出两种不同的表达类型。与配对的原发性肿瘤相比，G1亚型的复发性肿瘤未显示表达改变。相比之下，G2亚型的复发性肿瘤表现出从增殖型到神经元样型的表达变化。我们还观察到G1复发性肿瘤中干性相关基因的表达以及G2复发性肿瘤中DNA修复基因（即AURK、HOX、MGMT和MSH6）的表达改变，这可能以亚型特异性方式导致肿瘤复发过程中耐药机制的获得。我们认为，复发性胶质母细胞瘤在肿瘤复发期间可能会选择两种不同的转录组重编程策略来逃避化疗。我们的结果可能有助于确定针对异质性胶质瘤复发的个性化治疗策略。
